Chlamydia trachomatis is a sexually-transmitted bacterium that infects epithelial cells lining the genital tract to cause infertility and pelvic inflammatory disease in a proportion of infected women. Recent studies have also identified chlamydial infection as a cofactor in susceptibility to sexually-transmitted HIV. Efforts to develop a protective vaccine against this pathogen have been unsuccessful due to selection of candidate vaccines on the basis of antibody induction rather than stimulation of CD4+ T cell responses, which are now known to be the primary mechanism of immunity to Chlamydia. The purpose of the current project is to identify specifically those CD4+ T cell-derived mediators that are required for elimination of genital Chlamydia infections to provide a more rational basis for vaccine development. Toward this end, we have utilized mouse strains bearing targeted mutations in genes encoding a variety of immunologically-relevant mediators and measured the effect of these deletions on bacterial clearance. If mutant mice were unavailable, monoclonal antibodies specific for the molecule of interest were administered in vivo to provide functional interference instead. Results indicated that deletion of IL-12, a macrophage-derived cytokine critical in the induction of type 1 CD4+ T cell immunity, significantly inhibited chlamydial clearance. In contrast, deletion of IL-4, which is a cytokine involved in the type 2 pathway of CD4+ T cell immunity, had no effect. Interestingly, mice deficient in interferon-gamma, a major type 1 cytokine, cleared genital infections similarly to controls but developed disseminated chlamydial disease. These findings indicate that IL-12-driven, type 1 CD4+ T cell immunity is required for genital clearance of Chlamydia. Interferon-gamma may be important to prevent systemic dissemination of bacteria by macrophages but is not required for the elimination of an epithelial infection.